CN105246466B - Neo-synephrine particle with coating and its purposes in pharmaceutical preparation - Google Patents
Neo-synephrine particle with coating and its purposes in pharmaceutical preparation Download PDFInfo
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- CN105246466B CN105246466B CN201480015804.7A CN201480015804A CN105246466B CN 105246466 B CN105246466 B CN 105246466B CN 201480015804 A CN201480015804 A CN 201480015804A CN 105246466 B CN105246466 B CN 105246466B
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- Prior art keywords
- neo
- synephrine
- particle
- coating
- dosage
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- 210000003128 head Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 201000004920 hematocele of tunica vaginalis testis Diseases 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000003750 lower gastrointestinal tract Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 229960005016 naphazoline Drugs 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 150000002871 norepinephrines Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960002698 oxatomide Drugs 0.000 description 1
- BAINIUMDFURPJM-UHFFFAOYSA-N oxatomide Chemical compound O=C1NC2=CC=CC=C2N1CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BAINIUMDFURPJM-UHFFFAOYSA-N 0.000 description 1
- 229960003684 oxedrine Drugs 0.000 description 1
- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 229960003045 oxomemazine Drugs 0.000 description 1
- 238000007415 particle size distribution analysis Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940107333 phenergan Drugs 0.000 description 1
- 229960003534 phenindamine Drugs 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229940055447 phenylephrine hydrochloride 2.5 mg Drugs 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960003598 promazine Drugs 0.000 description 1
- CMDGQTVYVAKDNA-UHFFFAOYSA-N propane-1,2,3-triol;hydrate Chemical compound O.OCC(O)CO CMDGQTVYVAKDNA-UHFFFAOYSA-N 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 229960000230 sobrerol Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 229940089453 sudafed Drugs 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960003785 thonzylamine Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- OMDMTHRBGUBUCO-UHFFFAOYSA-N trans-sobrerol Natural products CC1=CCC(C(C)(C)O)CC1O OMDMTHRBGUBUCO-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- General Chemical & Material Sciences (AREA)
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Abstract
The invention discloses the neo-synephrine particle suitable for solid, semisolid or liquid dosage form.
Description
Technical field
The present invention relates to the neo-synephrine particle suitable for solid, semisolid or liquid dosage form.What can be wrapped by goes
Oxygen adrenaline particle can provide the speed of pharmaceutically suitable blood concentration to discharge deoxidation kidney within the period of extension
Upper parathyrine.The invention further relates to for preparing the method for the formulation for including neo-synephrine particle and being related to for utilizing mouth
The formulation of clothes administration mitigates the nasal cavity of human subject and the method that respiratory tract is congested.The formulation may also include one or more attached
The therapeutically active agent added, the additional therapeutically active agent be selected from antihistamine, decongestant, anodyne, antiinflammatory, antipyretic,
One or more in antitussive and expectorant.
Background technology
Neo-synephrine is that potent vasoactive shrinks medicine, and there is direct sympathomimetic nerve effect and indirect sympathomimetic nerve to imitate
Answer [Hoffman 2001].Dominant effect and direct effect excitement α 1- adrenocepters.Stimulate the capacity blood positioned at schneiderian membrane
The α 1- adrenocepters of pipe (post capillary venules) cause vessel retraction, blood volume to reduce, the reduction of the volume of schneiderian membrane
(nasal cavity mitigates congested) [Johnson 1993].The blood vessel of diminution allows a small amount of liquid to carry out nose, pharyngeal and sinus liner, and this is just
Cause nose film inflammation to reduce and reduce mucus and produce [Johnson 1993].Therefore, nasal cavity (is predominantly located at by vasoconstriction
Those in passage), neo-synephrine causes nasal congestion to mitigate [Hoffman 2001, Empey 1981].
Neo-synephrine is the first kind (generally recognized as safe and effective (GRASE)) oral nasal cavity congestion of OTC (OTC)
Agent.For the whole world, neo-synephrine has just obtained early in nineteen sixties, and from after 1996, deoxidation
Adrenaline is widely used in the U.S..It is widely used in the hydrochloric acid deoxidation adrenal gland of OTC adults and infantile cough and flu medicament
Element shows to can be used for respite due to common cold, hay fever, other upper respiratory tract allergy (anaphylaxis for adult and children
Rhinitis) caused by nasal congestion.10mg tablets for the oral administration of adult are commercially available.Dosage regimen is every four hours
The neo-synephrine of 10mg dosage, 60mg (six dosage) was no more than in 24 hours.Complete information is used in mark
Obtained in the OTC monographs of the medicine of approval.
Neo-synephrine, chemical name (R) -1- (3- hydroxy phenyls) -2- methylethanolamines can be commercially available with hydrochloride.
Chemical formula is C9H13NO2HCl and molecular weight is 203.67.The compound is white to pale white crystals powder, and it has
There is following chemical constitution:
The main metabolic pathway of neo-synephrine is to carry out sulfate by A types and monoamine oxidase B to be conjugated (mainly
In intestinal wall) and oxidative deamination [Suzuki 1979].Glucuronidation also occurs, but degree is smaller.In a research,
After 30mg dosage is administered orally more than eight hours [Ibrahim 1983], neo-synephrine is metabolised to deoxygenate on kidney respectively
Parathyrine-sulfate (the 47% of dosage), m- hydroxymandelic acids (the 30% of dosage), neo-synephrine-glucuronidase (dosage
12%) and m- hydroxyls-benzoglycols-sulfate (the 6% of dosage).Deamination is the main generation of intravenous injection neo-synephrine
Thank to approach [Hengstmann 1982], and the main path for oral administration is conjugated in sulfate.Neo-synephrine is in human body
I phases and II phase metabolins be shown below.Percent value in schematic diagram refers to the percentage of oral dose, such as
What Ibrahim was reported.
Release neo-synephrine be used for be grown up clinical test the effect of as shown by data neo-synephrine be effective nose
Chamber decongestant.
Paracetamol is the P-aminophenol derivatives with analgesic and antipyretic activity.It is used for temporarily mitigate with it is general
The associated mild pain of logical flu, backache, headache, toothache, menstrual pain;DOMS;And for temporarily mitigating joint
Scorching mild pain, and for bringing down a fever.In the U.S., the adult human dose of paracetamol is every 4 to 6 hours 1000mg, its
In in 24 hours maximum dose be 4000mg.The adult human dose of extended release paracetamol is 1300mg for every eight hours, wherein
Maximum dose is 3900mg in 24 hours.
Paracetamol is mainly metabolized by liver via three major parallel approach:Glucuronidation, sulfation
With oxidation [Miners 1983;Slattery 1989;Lee 1992;Miners 1992].Glucuronidated and oxidation are observed
First-order rate process, this refers to that the concentration of be metabolized paracetamol increases with the increase of concentration in liver.Sulfate
Approach observes michaelis-Menton kinetics, and this refers to once the concentration in liver exceedes saturated level, the paracetamol being metabolized
Concentration is maintained for constant.
The schematic diagram of metabolism of acetaminophen is shown below.Therapeutic dose less than 9% is through urinating prototype excretion
[Miners 1992].Main metabolic pathway is glucuronidation, wherein the paracetamol and glucose of 47% to 62% dosage
Thuja acid enzyme is conjugated.These glucuronidase conjugates are inactive and avirulent [Koch-Weser 1976], and in courage
Secrete in juice and eliminated through urine.Glucuronidase is conjugated mainly to be urged by one of isotype of glucosyltransferase (UGT1A6)
Change [Court 2001], wherein UDP Artogicurol is as primary co-factor.
Second main path of metabolism of acetaminophen is sulfation, wherein 25% to 36% dosage to acetyl ammonia
Base phenol is conjugated with sulfate.These sulphate esters conjugates are also inactive and avirulent [Koch-Weser 1976], and
And it is easy to through homaluria.Sulfation is mediated by sulfotransferase, and the sulfotransferase is foreign cell lyase, and 3 '-phosphorus
Adenosine monophosphate 5 '-phosphate is co-factor.The speed control factor of paracetamol sulfation is the activity of sulfotransferase
Rather than the consumption [Blackledge 1991] of sulfate.
3rd approach is oxidation, wherein the paracetamol of 5% to 8% dosage passes through cytochrome P-450 enzyme system
Metabolism.Cytochrome P-450 isodynamic enzyme primarily responsive to metabolism of acetaminophen is CYP2E1 [Manyike 2000].When right
When Paracetamol is metabolized by CYP2E1, it forms the intermediate of high activity, N- acetyl group 1,4-benzoquinone imines (NAPQI).By
It is high activity in NAPQI, therefore it can not can not also gather in liver external pelivimetry.The intermediate is by being stored in liver cell
Glutathione rapid inactivation, to form the conjugate [Koch-Weser of inactive and nontoxic cysteine and metabolin
1976].These conjugates are through homaluria [Mitchell 1974].
Neo-synephrine needs low frequency to be administered.Low frequency administration produces improved patient compliance.In addition, compared to
The blood level of seen fluctuation when giving multiple dose routine immediate release formulations, the consistent therapeutic blood level of active component can be more
It effectively and can even more produce Expected Results.Lasting level of significance can reduce seen in the case of peak value blood level
The seriousness and frequency of side effect.Therefore, it is necessary to can the low neo-synephrine of administration frequency preparation, for example, every 6,8,12,
16th, it is administered once within 20 or 24 hours.
Also need to match the duration of neo-synephrine using following active material, the active material provides ratio and is
Release the duration of neo-synephrine length.
Schering-Plough Corporation US published patent application 20070281020 discloses bag
Neo-synephrine containing 30mg, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, Kollidon CL-M, colloidal silica
With the sustained release tablets of magnesium stearate deoxidation is released for medication and sustained release tablets and the 10mg dosage three times of human subject
Adrenergic comparison.
McNeil-PPC, Inc. United States Patent (USP) 8,282,957 are disclosed comprising PHENYLEPHRINE HYDROCHLORIDE, modified starch
With Eudragit NE30DTMBand coating neo-synephrine particle and its including the formulation comprising paracetamol
Purposes in pharmaceutical dosage form, the neo-synephrine particles coat of band coating have comprising Eudragit RS PO, acetyl lemon
First coatings of sour tributyl and magnesium stearate and include Eudragit NE30DTM、Eudragit FS30DTM, stearic acid
Second coatings of magnesium, NaLS and Simethicone.
Warner Lambert Company United States Patent (USP) 6,001,392 is disclosed comprising cladding and uncoated and diethyl
The Amberlite of alkenyl benzene crosslinkingTMMedicine/resin complexes of IR69 mixture.
Schering-Plough Corporation US published patent application 20100068280 discloses bag
Pharmaceutical dosage form containing the neo-synephrine in sustained release forms.According to embodiment, in bioequivalence Journal of Sex Research, the bag of single dose
Neo-synephrine containing 30mg, lactose monohydrate, Methocel K100M CR, the tablet of Klucel EXF and magnesium stearate
In neo-synephrine immediate-release tablet formulations of the neo-synephrine compared to the 4 hours 10mg twice in interval.
The Sovereign Pharmaceuticals US published He of patent application 20050266032
20060057205 disclose the pharmaceutical dosage form comprising neo-synephrine., will using such as kayexalate according to embodiment
Neo-synephrine is attached in ion exchange resin complexes, and utilizes slowbreak polymer, such asL 100、MAE andCPD cladding coatings.The formula of the embodiment include 45mg sustained release neo-synephrine and
15mg releases neo-synephrine.
Tris Pharma, Inc. United States Patent (USP) 8,062,667 disclose the drug-ion exchange resin with coating and answered
Compound.According to embodiment, neo-synephrine is attached in ion exchange resin complexes using kayexalate, and
And utilize KOLLICOATTMSR-30D, glycerol triacetate and water are coated.
McNeil-PPC, Inc. United States Patent (USP) 8,394,415 disclose comprising i.e. release ibuprofen and are coated with the first He
The liquid preparation of extended release neo-synephrine-specific ion exchanger resin compound of second coatings (including special component).
McNeil-PPC, Inc. U.S. Patent application 11/761,698 disclose comprising brufen (IR) and are coated with bag
The solid compositions of the neo-synephrine of the first coatings containing ethyl cellulose and the second coatings comprising protectiveness coating
Thing.
Schering-Plough Healthcare Products, the Inc. disclosure of U.S. Patent application 20100068280
Compare via EnterionTMCapsule, 10mg Sudafed PETMDerivative 10mg PHENYLEPHRINE HYDROCHLORIDEs and via
EnterionTMThe bioavailability study of 30mg PHENYLEPHRINE HYDROCHLORIDEs derived from capsule.
Coating Place, Inc. U.S. Patent application 2007014239, which disclose, to be used for one or more medicines
Ion-exchange resin particles are loaded into form the method and composition of load medicated resin particle.
Continue need for the neo-synephrine product with above-mentioned attribute.
The content of the invention
The present invention relates to neo-synephrine or its pharmaceutically acceptable salt are delivered into person under inspection in need thereof,
To provide the peak blood drug level of following neo-synephrine after intake:About 0.1 to about 16 hour, preferably from about 0.5 to
About 5 hours, more preferably from about 1 to about 4.5 hour, and keep the level of neo-synephrine to be greater than about 20, about after intake
40th, about 60, about 80, about 100, about 120, about 140, about 160, about 180 or about 200pg/mL continue at least about 6, about 8, about 12, about
16th, about 20 and/or about 24 hours.
According to preferred embodiment, the present invention relates to the resin acid neo-synephrine particle with coating, what the band was coated
Resin acid neo-synephrine particle by neo-synephrine or its pharmaceutically acceptable salt be delivered to it is in need thereof by
Inspection person, to provide the peak blood drug level of following neo-synephrine after intake:About 0.1 to about 16 hour, preferably from about
0.5 to about 5 hour, more preferably from about 1 to about 4.5 hour, and keep the level of neo-synephrine to be greater than about after intake
20th, about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180 or about 200pg/mL continue at least about 6, about 8, about
12nd, about 16, about 20 and/or about 24 hours.
The invention further relates to the pharmaceutical dosage form for including neo-synephrine particle, the neo-synephrine particle will deoxygenate kidney
Upper parathyrine or its pharmaceutically acceptable salt are delivered to person under inspection in need thereof, to provide following deoxidation after intake
Adrenergic peak blood drug level:About 0.1 to about 16 hour, preferably from about 0.5 to about 5 hour, more preferably from about 1 to about 4.5 is small
When, and keep the level of neo-synephrine to be greater than about 20 after intake, about 40, about 60, about 80, about 100, about 120, about
140th, about 160, about 180 or about 200pg/mL continues at least about 6, about 8, about 12, about 16, about 20 and/or about 24 hours.
In another embodiment, it will thus provide the neo-synephrine particle of the neo-synephrine of extended release is with being in release shape
The neo-synephrine mixing of formula.
In another embodiment, it is neo-synephrine particle and one or more additional therapeutic agents is (a kind of or more
Kind) mixing, for releasing or being sustained.Released when this medicament or various medicaments are configured into intake, in colon it is adjoint extremely
Few a part of neo-synephrine sustained release, or any combination of them.In one embodiment, additional therapeutic agent does not wrap
Cover.In another embodiment, additional therapeutic agent is wrapped by.
Additional therapeutic agent can be antihistaminic, decongestant, anodyne, antiinflammatory, antipyretic, anti-tussive agents, expectorant,
Or any other therapeutic agent;Or can be for mitigating flu, seasonal allergic and other allergy, hay fever or Dou Wenti
The medicament of symptom;The medicament for the symptom that nasal mucus can be caused to increase can be mitigated.Preferably, one or more additional therapeutic agents are pair
Paracetamol.
The example of antihistamine and decongestant include but is not limited to Brompheniramine, chloreyclizine, dexbrompheniramine, bromine oneself
Newly, phenindamine, pheniramine, mepyramine, Thonzylamine, pripolidine, ephedrine, d-pseudo-ephedrine, phenylpropanolamine, flutter
That is quick, dextromethorphan, diphenhydramine, doxylamine, astemizole, teldane, Fexofenadine fourth, Naphazoline, hydroxymethyl thiazole
Quinoline, Montelukast, third monarch, phenacrylamide, Clemastime Fumartis, Acrivastine, phenergan, Oxomemazine, mequitazine, Bu Ke
Power piperazine, bromhexine, Ketotifen, teldane, Ebastine, oxatomide, Xylometazoline, Loratadine, decarboxylation loratadine
And cetirizine;Their isomers;And their pharmaceutically acceptable salt and ester.
The example of suitable anodyne, antiinflammatory and antipyretic includes but is not limited to:NSAIDs (NSAID), such as
Propanoic derivatives are (for example, brufen, naproxen, Ketoprofen, Flurbiprofen, fenbufen, fenoprofen, indoprofen, ketone Lip river
Sweet smell, Fluprofen, than the third sweet smell, Carprofen,Promazine, pranoprofen and suprofen) and COX inhibitor, such as celecoxib;To acetyl
Amino phenols;Acetylsalicylic acid;Acetogenin, such as Indomethacin, Diclofenac, sulindac and tolmetin;Fenamic acid derivative,
Such as mefenamic acid, Meclofenamic Acid and Flufenamic acid;Biphenylcarboxylic acid derivatives, such as Diflunisal and Flufenisal;With former times health class, such as
Piroxicam, Sudoxicam, isoxicam and Meloxicam;Their isomers;And their pharmaceutically acceptable salt
And prodrug.
The example of antitussive and expectorant includes but is not limited to:Diphenhydramine, dextromethorphan, narcotine, chlophedianol,
Menthol, benzonatate, dionin, codeine, acetylcysteine, S-Carbomethylcysteine, ambroxol, belladonna alkaloids,
Sobrerol, guaiacol and guaiacol glycerol ether;Their isomers;And their pharmaceutically acceptable salt is with before
Medicine.
Another aspect of the invention is flu, influenza, allergy or the non-mistake for treating person under inspection in need thereof
The method of the symptom of quick property rhinitis, this method include applying the neo-synephrine particle of the present invention.In certain embodiments, go
Oxygen adrenaline particle is administered for often about 6,8,12,16,20 or 24 hours.In a preferred embodiment, deoxygenate on kidney
Parathyrine particle is administered for often about 12 hours.In another preferred embodiment, resin acid neo-synephrine particle often about 8
Hour is administered.
Certain embodiments of the present invention has lasting bioavilability for holding neo-synephrine in person under inspection's body
Method, this method includes orally administering person under inspection at least one of neo-synephrine particle, wherein neo-synephrine
Divide in colonic absorption, and wherein neo-synephrine is dense in self serum when 6 hours after applying said composition
Spend at least about 20, about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180 or about 200pg/mL.Specific
In embodiment, concentration of the neo-synephrine in self serum is at least about when about 8 hours after applying said composition
20th, about 40, about 60, about 80, about 100, about 120, about 140, about 160, about 180, about 200pg/mL.In a particular embodiment, exist
Using after said composition at 12 hours concentration of the neo-synephrine in self serum be at least about 20, about 40, about 60,
About 80, about 100, about 120, about 140, about 160, about 180, about 200pg/mL.In a particular embodiment, apply said composition it
Afterwards 20 hours when concentration of the neo-synephrine in self serum be at least about 20, about 40, about 60, about 80, about 100, about
120th, about 140, about 160, about 180, about 200pg/mL.In a particular embodiment, gone when 20 hours after applying said composition
Concentration of the oxygen adrenaline in self serum be at least about 24, about 40, about 60, about 80, about 100, about 120, about 140, about
160th, about 180, about 200pg/mL.Some other embodiments of the present invention are that neo-synephrine is administered to the side of person under inspection
Method, this method include oral neo-synephrine particle, and at least some neo-synephrines are delivered to colon by said composition, this
Sample neo-synephrine discharges and by colonic absorption in colon.
The present invention can be more fully understood with reference to accompanying drawing hereafter, embodiment and example.
Brief description of the drawings
Fig. 1 is shown deoxygenates adrenal gland in extended release (ER) resin acid for applying the coating of the band comprising 20mg neo-synephrines
The mean blood plasma concentration curve of neo-synephrine during crude granule.Referring to Fig. 1, the neo-synephrine that y-axis represents to dissociate is in blood
Concentration in slurry (unit is pik (pg) every milliliter (mL)).X-axis represents the time (unit is hour).Fig. 1 was shown at 2 hours
When neo-synephrine reach peak value (Cmax) mean concentration.Fig. 1 also show the second peak value at about 12 hours.
Fig. 2, which is shown, is applying the ER resin acid neo-synephrine particles of the coating of the band comprising 20mg neo-synephrines
When neo-synephrine individual plasma concentration curve.Referring to Fig. 2, the fluctuation between individual is advantageous to tune and releases deoxidation adrenal gland
Element.Cmax scope produced at about 1 hour to about 4.5 hours.The second peak value of whole persons under inspection was observed at about 12 hours.
Fig. 3 is shown when applying the ER PHENYLEPHRINE HYDROCHLORIDE particles of the coating of the band comprising 20mg neo-synephrines
The individual plasma concentration curve of neo-synephrine.Referring to Fig. 3, dotted line is the curve from Fig. 1, for omparison purpose.See
Observing neo-synephrine particle has slightly higher Cmax.At about 12 hours, it was observed that the second peak value of two curves.This can
Can be because due to particle along quick the moving of intestines and stomach and a small amount of neo-synephrine by intestinal wall by preceding systemic metabolism.Deoxidation
Adrenaline will cause have higher absorption in the time later in the release of colon.
Fig. 4 is shown when applying the ER PHENYLEPHRINE HYDROCHLORIDE particles of the coating of the band comprising 20mg neo-synephrines
The individual plasma concentration curve of neo-synephrine.
Fig. 5, which is shown, is applying the ER resin acid neo-synephrine particles of the coating of the band comprising 15mg neo-synephrines
With the deoxidation adrenal gland after the liquid IR PHENYLEPHRINE HYDROCHLORIDE (" ER-IR blends ") comprising 5mg neo-synephrines
The mean blood plasma concentration curve of element.Referring to Fig. 5, solid line represents ER-IR blends.Equally, the curve of the therapeutic scheme is with being directed to
Resin acid is consistent with curve seen by salt acid supplement.For ER-IR blends, two peaks in initial 2 hours be present
Value;One essentially from IR dosage and another accumulation from IR and ER dosage.Cmax is faster reached and is kept longer
Period.Therefore, ER-IR blends seem to be beneficial in that the time limit of action.
Fig. 6, which is shown, is applying the ER resin acid neo-synephrine particles of the coating of the band comprising 15mg neo-synephrines
With the individual blood concentration of the neo-synephrine after the liquid IR PHENYLEPHRINE HYDROCHLORIDE comprising 5mg neo-synephrines
Curve.
Fig. 7 shows and deoxygenated when applying the liquid IR PHENYLEPHRINE HYDROCHLORIDE particle comprising 20mg neo-synephrines
Adrenergic individual plasma concentration curve.Referring to Fig. 7, solid line represents currently marketed IR fluid products, and dotted line is
Curve from Fig. 5 is for comparing.The Cmax of ER-IR blends is less than the Cmax of IR forms.
Fig. 8 shows and deoxygenated when applying the liquid IR PHENYLEPHRINE HYDROCHLORIDE comprising 20mg neo-synephrines on kidney
The individual plasma concentration curve of parathyrine.
Fig. 9, which is shown, is applying the ER resin acid neo-synephrines of the coating of the band comprising 22.5mg neo-synephrines
When grain and liquid IR PHENYLEPHRINE HYDROCHLORIDE (" ER-IR blends ") comprising 7.5mg neo-synephrines with apply comprising
The average blood medicine for the neo-synephrine being compared during the liquid IR PHENYLEPHRINE HYDROCHLORIDE of 20mg neo-synephrines is dense
Write music line.
Figure 10 A and 10B show the mean blood plasma concentration curve of the following neo-synephrine of comparison, i.e., (1) is in administration bag
The ER resin acid neo-synephrine particles of the band coating of the neo-synephrine containing 15mg and the liquid for including 5mg norepinephrines
(Figure 10 A) and (2) is applying the ER trees of the coating of the band comprising 22.5mg neo-synephrines during body IR Arterenol (Hoechst)s
When resin acid neo-synephrine particle and liquid IR PHENYLEPHRINE HYDROCHLORIDE comprising 7.5mg neo-synephrines (Figure 10 B)
The comparison of the liquid IR PHENYLEPHRINE HYDROCHLORIDE of 20mg neo-synephrines is included with (3).
Figure 11 compares the mean blood plasma concentration curve of following neo-synephrine, i.e., includes going for 15mg in administration (1)
The ER resin acid neo-synephrine particles of the adrenergic band coating of oxygen and the liquid IR hydrochloric acid comprising 5mg neo-synephrines
With deoxygenating adrenal gland in the ER resin acids for applying the band coating that (2) (a) includes 15mg neo-synephrines during neo-synephrine
Crude granule, (b) include the liquid IR PHENYLEPHRINE HYDROCHLORIDE and (c) 1300mg ER acetparaminosalol of 5mg neo-synephrines
The comparison during combination of phenol.
Embodiment
It is believed that those skilled in the art can make full use of the present invention on the basis of being described herein.Following specific implementation
Example is construed as what is be merely exemplary, and anyway all without limiting remainder of this disclosure in any way.
Unless otherwise defined, all technologies used herein and scientific terminology have the technical field of the invention public
The identical meanings known.In addition, by all publications being mentioned above, patent application, patent and other bibliography with the side of reference
Formula is incorporated herein.Except as otherwise noted, otherwise all percentages used herein are by weight.It is in addition, as shown herein
All scopes are intended to any combination of the value between two end points (including including end points).
Definition
As used herein, the pharmaceutically acceptable salt of neo-synephrine includes but is not limited to phenylephrine salt acid
Salt, neo-synephrine biatrate, neo-synephrine tannate etc..In a preferred embodiment, deoxygenate on kidney
The pharmaceutically acceptable salt of parathyrine is phenylephrine hydrochloride.
As used herein, for any specific drug, " AUC " means derived from the medicine calculated by trapezoidal rule
Dosage or active " area under Cot curve " relative to time point.AUC is to show that medicine changes over time tired
The parameter of hematocele concentration, and indicate total amount and availability of the medicine in blood plasma.
As used herein, " Cmax " means testing after medicine has been applied and in the prodrug for applying the second dosage
Maximum (or peak value) concentration reached in region.
As used herein, " crystal form " means the active component of non-amorphous form so that it shows crystalloids
The ability of matter, including but not limited to diffraction visible ray.Crystal can be additionally used in active component of the description in its purified form, i.e.,
(such as) added without other excipient to wherein.
" slowbreak " is referred to, it means after application, and at least a period of time active component does not discharge from formulation, i.e. active component
Release be not to occur immediately after oral administration.
As used herein, " dissolution medium " means any suitable liquid environment, in this context supensoid agent of the invention
Type can dissolve, for example, In Vitro Dissolution medium or gastro-intestinal Fluid for determining product.For determining one or more active components
Include those described by American Pharmacopeia from the suitable In Vitro Dissolution medium of mixed suspension form dissolution of the present invention.
As used herein, " dosage ", " formulation " or " dosage " means to include the medicine of therapeutically active agent (one or more)
Amount of the composition in administration." dosage ", " formulation " or " dosage " is included when one or more pharmaceutical compositions are administered simultaneously
Dosage.In one embodiment, formulation is tablet.In one embodiment, formulation is multilayer tablet.Including multilayer tablet
Embodiment in, one layer can include i.e. release part and another layer can include extended release part.In the embodiment including multilayer tablet
In, one layer may include resin acid neo-synephrine particle, and another layer neo-synephrine for may include to release form and/
Or second active component.In one embodiment, the formulation comprising resin acid neo-synephrine particle is the soft of liquid filling
Gel.
As used herein, " drug-resin complex " mean active component (include but is not limited to active constituents of medicine) with
The combining form of ion exchange resin.Drug-resin complex is also known as " resinate (resinate) " in the art.
Ion exchange resin that can be used according to the invention is AmberliteTMIRP 69 (The Dow Chemical Company),
With insoluble, highly acid, it is the sodium form cation exchange tree of the sulfonated copolymer derived from styrene and divinylbenzene
Fat.Movable or tradable cation is sodium, and it can have the cation (alkalescence) of numerous species to exchange or replace, the cation
Including such as copper, zinc, iron, calcium, strontium, magnesium and lithium.By on Drug absorbability to ion-exchange resin particles to form medicine/resin compounded
Thing is well known technology, such as United States Patent (USP) 2,990,332 and 4, shown in 221,778.Generally, by the aqueous suspension of medicine and resin
Liquid mixes, and then washs and dry the compound.Can by measure reaction medium pH change, or by measure sodium or
The concentration of medicine changes, to being detected on Drug absorbability to resin.Collect formed medicine/resin complexes and profit
With ethanol and/or water washing, to ensure to remove any uncombined medicine.Generally by compound in pallet in room temperature or high temperature
It is lower to air-dry.Neo-synephrine in medicine/resin complexes is about 0.25 relative to the ratio of resin:1 to about 0.65:1, it is excellent
Choosing about 0.30:1 to about 0.55:1, preferably from about 0.35:1 to about 0.45:1.
" enteric " means greater than about 5.0 or greater than about 5.5 or greater than about 6.0 or to be present in molten under the pH in enteron aisle
Solution.
" extended release " is referred to, it means after application, and active component is discharged in a manner of substantially continuous, controlled from formulation
Out, and active component is more related than the instant-free formulation to identical component from the time of formulation release completion (exhausting)
The time it is longer.The type of extended release includes control release, sustained release, extends release, Zero order release, first-order release, pulse
Formula release etc..
As used herein, " quick-release " means that the dissolution feature of at least one active component meets the speed containing the active component
Release the USP regulations of matrix agent.It is dissolvable in water with the active component for releasing property in gastrointestinal contents, it is not intended to which delay extends work
The dissolution of property composition.
" liquid dosage form " can non-exclusively include supensoid agent or elixir, one or more of which active component is dissolved,
It is partly dissolved or in state that is undissolved or suspending.
As used herein, " tune is released " should apply to active component release or dissolution in the dissolution medium (such as gastro-intestinal Fluid) and change
Become.The type released is adjusted to include:1) extended release;Or 2) slowbreak.Generally, preparing adjusts release dosage form to cause active component (one or more)
It can be utilized within the time cycle of extension after intake, this relative to identical active component in regular dosage form so that apply
With administration frequency is reduced.Adjust release dosage form also enable using one of which active component duration can with it is another activity into
Point duration different active component combination.
As used herein, " pharmacodynamics " or " PD " relation between the drug concentration and gained effect of site of action
Research.
As used herein, " pharmacokinetics " or " PK " is drug absorption, distribution, metabolism and the time course of excretion.
As used herein, term " neo-synephrine " refers to benzyne methanol 3- hydroxyl-alphas-[(methylamino) methyl], and
Including but not limited to its pharmaceutically acceptable salt, ester, isomers or derivative.
As used herein, medicine " rate of release " refers to the amount that time per unit medicine discharges from formulation, as released per hour
The milligram number (mg/hr) for the medicine put.Drug release rate is counted under the conditions of the vitro dosage form solubility test being known in the art
Calculate.As used herein, the drug release rate obtained in " after the administration " stipulated time refers in suitable dissolution test (such as USP
24(United States Pharmacopeia 24,United States Pharmacopeia Convention,Inc.,
Rockville, MD) in list those) start after, the stipulated time obtain vitro drug release speed.
As used herein, " semipermeability " means in film and suitable dissolution medium (such as gastro-intestinal Fluid or In Vitro Dissolution medium)
During contact, water can penetrate, and other molecules (including salt described herein and active component) can slowly spread to pass through and be somebody's turn to do
Film.
" semisolid dosage form " means high viscosity and some properties with liquid formulations, and these properties include but unlimited
In:(1) there is the ability for substantially conforming to and applying pressure to object thereon;(2) lack readily flowed as liquid
Ability.Semisolid dosage form also has some properties of solid, including but not limited to higher density and the shape determined.Half
Solid dosage forms can nonexcludability include:It is gel, Chewy formulation, pectin base Chewy formulation, candy type Chewy formulation, moldable
Gelatine type formulation.
" solid dosage forms " means to be substantially at room temperature solid and has the formulation of at least about 0.5g/cc density.Gu
Body formulation can non-exclusively include:Capsule, powder or the grain that tablet, capsule shape medicament, powder or the particle of agglomeration fill
Wafer, compressed tablets, coated tablet, chewable formulation and the Expidet of son filling.
As used herein, less than about 20% is meant " substantially with coating " on particle, such as less than about 15%, or it is few
It is exposed in about 1.0% particle surface, does not have such as with required coating covering.As used herein, when for required coating
When, term " substantially cover " or " substantially continuous " mean that coating is generally continuous and substantially cover core or bottom
Whole surface so that seldom exposed to no active component or bottom.Lamination can be carried out by being applied to the coating of particle, wherein each
Layer is prepared in aqueous (water base) system or organic solvent system and sequentially added, until reaching required coating level.
As used herein, " curative effect " means to be intended to diagnose, treats, cures, relaxing or prevention disease or the knot for influenceing body
Structure or any effect of the active component of any function or effect.
The specific embodiment of the present invention is shown by following instance.The present invention is not limited to shown in these examples
The specific restriction gone out.
Example
Neo-synephrine extended release particle preparation is shaped, to be formulated into liquid dosage form and solid dosage forms.Deoxygenate kidney
Upper parathyrine extended release particle can be used to match duration, the work together with other active materials (especially pain active material)
Property material can provide the duration longer than neo-synephrine.Such active material include but is not limited to paracetamol,
Brufen and naproxen, and their salt and derivative.
Example 1:The preparation of preparation comprising the neo-synephrine extended release particle with coating
Prepare the preparation for the neo-synephrine particle for being coated with polymer coating.It is proved to provide deoxidation adrenal gland
Element with extension period discharge preparation placed 24 months under conditions of relative humidity 60% at 25 DEG C and 40 DEG C in
Placed under conditions of relative humidity 75% and keep within 3 months stable.Many granulated formulations of neo-synephrine are over time
And unstable and generation significantly degraded.
The neo-synephrine particle (3.203g) of a collection of band coating is prepared according to the formula in table 1.Quantitative and batch formula
Shown respectively in table 1.
Table 1:Extended release neo-synephrine particle with coating1
1. the unit dose of the particle comprising 20mg PHENYLEPHRINE HYDROCHLORIDEs is about 377.4mg.Actual weight depends on
The measured quantity of PHENYLEPHRINE HYDROCHLORIDE in particle.
2. solid weight.
3. include ethyl cellulose, cetanol and NaLS.
4. purified water, acetone, isopropanol are removed during processing.
Particle it is laminated:
1. USP level purified waters are added to the rustless steel container of suitable dimension.
2. added under slight stirring NF levels ethyl acrylate and NF level methylmethacrylate copolymers dispersion (NE 30D)。
3. adding PHENYLEPHRINE HYDROCHLORIDE, while mix under agitation, and form mixture.
4. coat (laminated) NF level pre-paying modified starches using the mixture of step 3.
Dry and screen:
5. drying laminated PHENYLEPHRINE HYDROCHLORIDE/pre-paying modified starch derived from step 4 and by No. 20 sieves
Screened.
Laminated particle is coated using ethyl cellulose cladding solution:
6. they are added to the container of suitable dimension successively according to the order listed by following material under slight stirring:
USP level isopropanols, it is NF grade acetones afterwards, is NF level acetyltributyl citrates afterwards.
7. add under agitation NF levels ethyl celluloses (Standard Premium 10) and mix, directly
To forming settled solution.
8. magnesium stearate is added to the solution under agitation.
9. wrapped using the solution derived from step 8 using the suitable fluid bed coating unit with Wurster inserts
Cover laminated neo-synephrine/pre-paying modified starch particle of the screening derived from step 5.
Solidification:
10. the particle derived from step 9 is solidified in an oven.
Utilize NE30D and Aquacoat It is right Particle with coating is coated:
11. willNE30D is added to the container of suitable dimension, adds USP levels purified water and ethyl cellulose afterwards
Plain aqueous dispersion NF (Aquacoat) and mixed under gentle agitation.
12. derived from using cladding solution using the suitable fluid bed coating unit equipped with Wurster inserts to coat
Step 10Laminated particle with coating.
13. the particle that the band derived from step 12 is coated is mixed with NF level colloidal silicas.
Solidification:
14. the particle derived from step 13 is solidified in an oven.
Analysis of dissolution
The dissolution of 0 to 14 hour of the neo-synephrine particle that band of the analysis derived from step 14 is coated in the following manner
Degree:Use American Pharmacopeia<General rule<711>Dissolution rate>Described instrument, apparatus II, revolving vane, examined under 274nm using UV
Survey.It is 750mL 0.1N HCl in first hour dissolution medium, and is then situated between in dissolution in second hour to the 14th hour
Matter is 1000mL 0.05M sodium phosphate buffer.Temperature is 37 DEG C and rotary speed is 50rpm.Dissolution rate shows, the system
The percentage for the neo-synephrine that the content that the neo-synephrine discharged in agent is prepared relative to standard is 100% is such as
Under:It was less than or equal to 50% in 1 hour, 30% was more than or equal in 3 hours, and be more than or equal in 8 hours
50%.Method therefor is following and result is shown in table 2 below.
Dissolving-out method, USP instruments (2 blades, 50rpm)
1. checking dissolution medium temperature has reached desired value (37 DEG C).
2. weigh the sample equivalent to 45mg PHENYLEPHRINE HYDROCHLORIDEs.Sample is added on (on the surface of medium solution)
The container of the hydrochloric acid of 0.1N comprising 750mL and start dissolution rate test, wherein paddle speed is 50rpm.In 0.1N hydrochloric acid
It is middle operation 1 hour after, complete 1 hours point measurement.Carried out immediately by the tertiary sodium phosphate for the 0.20M for adding 250mL
Buffer stage.The pH of buffer medium should be 6.8 ± 0.05.
3. it is being situated between by using LEAP fiber optic systems (UV measurements are carried out under 274nm) measurement with line probe
The UV absorbances of the PHENYLEPHRINE HYDROCHLORIDE discharged in matter.
4. use the ratio of the UV absorbances for the sample solution being tested under 274nm wavelength and the absorbance of standard liquid
The amount of the PHENYLEPHRINE HYDROCHLORIDE of relatively result dissolution to determine.The amount of the PHENYLEPHRINE HYDROCHLORIDE of institute's dissolution can also be used
Following methods determine.
Table 2
Time (hour) | Dissolution rate % |
1 | 10%-30% |
2 | 30%-50% |
3 | 50%-70% |
4 | 60%-80% |
6 | 75%-95% |
8 | 85%-100% |
10 | 90%-100% |
12 | 90%-100% |
14 | 90%-100% |
Analysis method
Sample preparation
1. accurately weigh about 1600mg PHENYLEPHRINE HYDROCHLORIDE particle and be transferred in 200mL volumetric flasks.(recommend
1mL 1% acetic acid/water solution is added, with wet granulate, so as to avoid the formation of solid block).
2. add 70mL 1% acetic acid/acetonitrile solution;Low-speed oscillation 1 hour on platform rocker.Pay attention to:Periodically
Ground turn flask, with the particle assembled in elimination solvent level.
3. about 50mL 1% acetic acid/water solution is added to flask and continuous low-speed oscillation 1 hour.
4. it is diluted to scale with 1% acetic acid/water solution and is sufficiently mixed.
5. filter aliquot using 0.45 μm of miillpore filter Kynoar filter.Arranged first before filtrate is collected
Go out 1-2mL filtrate, for further dilution.
6. 6mL filtrate is transferred in 50mL volumetric flasks using pipette, quarter is diluted to for 1% acetic acid/water solution
Spend and be sufficiently mixed.
The analysis of neo-synephrine
Under the conditions of similar to those set forth below, by standard items, (the 0.05mg/mL hydrochloric acid in 1% acetic acid/water is gone
Oxygen adrenaline) and sample be injected on suitable HPLC system.Parameter can be changed to optimize chromatography.Use tested sample
The comparative result of the peak area of product solution and the peak area of standard liquid determines the content of PHENYLEPHRINE HYDROCHLORIDE.
HPLC chromatogram separation condition
Degradation products method
Sample preparation
2. accurately weigh about 1600mg PHENYLEPHRINE HYDROCHLORIDE particle and be transferred in 200mL volumetric flasks.(recommend
1mL 1% acetic acid/water solution is added, with wet granulate, so as to avoid the formation of solid block).
2. add 70mL 1% acetic acid/acetonitrile solution;Low-speed oscillation 1 hour on platform rocker.Pay attention to:Periodically
Ground turn flask, with the particle assembled in elimination solvent level.
3. about 50mL 1% acetic acid/water solution is added to flask and continuous low-speed oscillation 1 hour.
4. it is diluted to scale with 1% acetic acid/water solution and is sufficiently mixed.
5. filter aliquot using 0.45 μm of miillpore filter Kynoar filter.Arranged first before filtrate is collected
Go out 1-2mL filtrate, for further dilution.
6. 6mL filtrate is transferred in 50mL volumetric flasks using pipette, quarter is diluted to for 1% acetic acid/water solution
Spend and be sufficiently mixed.
The analysis of neo-synephrine
Under the conditions of similar to those set forth below, by standard items (the 0.00025mg/mL salt in 1% acetic acid/water
Sour neo-synephrine) and sample be injected on suitable HPLC system.Parameter can be changed tested to optimize chromatography use
Sample solution peak area and standard liquid peak area comparative result come determine the degraded of PHENYLEPHRINE HYDROCHLORIDE produce
The amount of thing.
HPLC chromatogram separation condition
Example 2:The preparation of resin acid neo-synephrine extended release particle with coating
Prepare the particle comprising neo-synephrine and cationic ion-exchange resin and further coated using semipermeable membrane.
The ratio of the amount of coating constituents can change to a certain degree, such as cellulose acetate:Hydroxypropyl cellulose can be 2:1、3:1、4:1 or
5:1.The coating level that can be made a change to a certain extent can be based on the weight of the particle with coating such as 50%, 45%,
40%th, 35%, 30%, 25% or 20%.The maximum particle size of the particle in cationic ion-exchange resin is originated at about 74 μm and about 177
Between μm (micron).
It is proved to provide 25 DEG C of the resin acid neo-synephrine particle that neo-synephrine discharges with the period of extension
Place 24 months under conditions of relative humidity 60 and placed at 40 DEG C under conditions of relative humidity 75% and keep within 3 months steady
It is fixed.Many granulated formulations of neo-synephrine are unstable over time and significantly degraded occurs.
The resin acid neo-synephrine particle (3.846kg) of a collection of band coating is prepared according to the formula in table 3.Quantitatively match somebody with somebody
Side and batch formula are shown in table 3 and table 4.
Table 3:The quantitative formula of resin acid neo-synephrine with coating
1. the unit dose of the particle comprising 20mg (A) and 15mg (B) PHENYLEPHRINE HYDROCHLORIDE is respectively about 84.2mg
And 63.2mg.The amount for the PHENYLEPHRINE HYDROCHLORIDE that actual weight is depended in the particle that measures.
2. quantity represents (the deoxidation kidney of sequestered of the 1mg PHENYLEPHRINE HYDROCHLORIDE equivalent to 0.821mg of sequestered
Upper parathyrine).
3. acetone and purified water are removed in processing procedure.
Table 4:Resin acid neo-synephrine batch formula with coating
Component | Weight (kg)/batch | Weight % (w/w) |
Sequestered neo-synephrine1 | 0.750 | 19.5 |
USP polystyrenes sodium sulfonate (granularity is about 74 μm to about 177 μm) | 1.750 | 45.5 |
NF level cellulose acetates | 1.0095 | 26.25 |
NF level hydroxypropyl celluloses | 0.3365 | 8.75 |
NF grade acetones3 | -- | -- |
USP level purified waters3 | -- | -- |
Amount to | 3.846 | 100.0 |
Sequestered neo-synephrine of the 1.1g PHENYLEPHRINE HYDROCHLORIDE equivalent to 0.821g.
2. acetone and purified water are removed in processing procedure.
The resin acid neo-synephrine particle with coating is prepared using following process:
Screening:
1. 170 eye mesh screens will be passed through with the USP polystyrenes sodium sulfonate for it is expected granularity and collection screen is remaining on the net
Part.
Washing:
2. the USP polystyrene sodium sulfonates derived from step 1 are dispersed in purified water and stirred.
3. upon agitation, filtering derives from a part of slurries of step 2 and utilizes USP levels purifying water washing.Continuous filtering,
Until most of water is removed.
4. transfer a resin into container.
5. repeat step 3 and step 4, until whole slurries are removed.
Medicine loads:
6. USP level purified waters are added in the rustless steel container of suitable dimension.
7. PHENYLEPHRINE HYDROCHLORIDE upon agitation, is added to container and stirred until dissolving.
8. addition derives from the resin of the washing of step 5 and stirs into slurries with continuous stirring.
9. upon agitation, take out a part of slurries derived from step 8 and utilize USP levels purifying water washing.Continuous filtering,
Until most of water is removed.
10. the resin acid neo-synephrine after the filtering of the washing derived from step 9 is transferred in container.
11. repeat step 9 and step 10, until whole slurries are filtered.
Dry:
12. dry resin acid neo-synephrine.
The preparation of cladding solution:
13. USP levels purified water and NF grade acetones are added to the rustless steel container of suitable dimension.
14. NF level hydroxypropyl celluloses are added slowly to container and stirred until dissolving.Slowly add NF levels
Cellulose acetate and stir until dissolving.
15. addition NF grade acetones reach required weight until the solution.
Cladding:
16. in the suitable fluid bed coating equipment equipped with Wurster posts, using the cladding solution derived from step 15 come
Resin acid neo-synephrine of the cladding derived from step 12.
17. the resin acid neo-synephrine with coating is discharged in container.
Dry:
18. the resin acid neo-synephrine of dry zone coating.
Screening:
19. the resin acid neo-synephrine of dry band coating is screened by 40 eye mesh screens of Unite States Standard and is collected
Through the part of screen cloth.
Analysis of dissolution
0 to 14 hour of the resin acid neo-synephrine particle that band of the analysis derived from step 19 is coated in the following manner
Dissolution rate:Use American Pharmacopeia<General rule<711>Dissolution rate>Described instrument, apparatus II, revolving vane, make under 274nm
Detected with UV.It is 750mL 0.1N HCl in first hour dissolution medium, and in dissolution in second hour to the 14th hour
Medium is 1000mL 0.05M sodium phosphate buffer (pH 6.8).Speed is 37 DEG C and rotary speed is 50rpm.Dissolution
Degree shows, the neo-synephrine that the content that the neo-synephrine discharged in said preparation is prepared relative to standard is 100%
Percentage it is as follows:It was less than or equal to 50% in 1 hour, 30% was more than or equal in 3 hours, and it is big in 8 hours
In or equal to 50%.Method therefor is following and result is shown in table 5 below.
Dissolution method, USP instruments 2 (blade), 50rpm
1. checking dissolution medium temperature has reached desired value.
2. sample is added to the container of the 0.1N of (on the surface of medium solution) comprising 750mL hydrochloric acid and started molten
Out-degree is tested, and wherein paddle speed is 50rpm.After 0.1N hydrochloric acid operates 1 hour, the sample of 1 hour is taken out, and immediately
The buffer stage is entered by the tertiary sodium phosphate for the 0.20M for adding 250mL.The pH of medium should be 6.8 ± 0.05.
3. respectively 1 hour, 3 hours, 6 hours (optional) and after 8 hours, the molten of 10mL is taken out from each container
Out-degree sample solution.Filter (10 μm) filtered sample solution is flowed completely out by Varian.
4. the UV absorbances of the neo-synephrine for comparing institute's dissolution under 274nm wavelength and standard liquid can be passed through
The amount of the neo-synephrine of UV absorbances dissolution to determine.Deoxidation kidney can also be used in the amount of the neo-synephrine of institute's dissolution
Upper parathyrine analysis method determines.
5. the amount in the dissolution of each time point institute is corrected by the amount of the addition taking-up at the point position of 3,6 and 8 hours.
Sampled for centre, use DISSL programs (or equivalents) or manual correction.
Table 5
Time (hour) | Dissolution rate % |
1 | 20%-40% |
2 | 40%-60% |
3 | 50%-70% |
4 | 60%-80% |
6 | 75%-95% |
8 | 80%-100% |
10 | 90%-100% |
12 | 90%-100% |
14 | 90%-100% |
Example 3:Particle size distribution analysis
Analyze the size distribution of some batches of resins and the particle based on resin.Sample includes:(1) can be from Dow Chemical
Commercially available AmberliteTM, (2) have the resin not loaded of selected granularity (as respectively by process A and process B
Prepare), and the resin particle (that is, comprising neo-synephrine) of (3) loading.Per sample using about 75 grams in FMC
Syntron screen analyzers (FMC Technologies, Houston, TX) analyze size distribution, wherein being set as 90 volts, continue 11
Minute.Screen cloth is handled using the magnesium stearate of slight efflorescence, to prevent from producing viscosity during operation.As a result in table 6 and 7
Show.
ATM L3P sound waves screening machine (Advantech Manufacturing, New Berlin, WI) such as can be used to analyze
Compared with the size distribution of small-scale, the ATM L3P sound waves screening machines are by using sound wave pulse, with reference to mechanical agitation, to be provided with
The particle separation of effect.
Table 6:The grain size analysis (wherein for " prototype " and selecting process A and B) for the resin not loaded
1.AmberliteTMIRP69 " prototype " is commercially available
2. " the Amberlite after process A " selection granularitiesTM IRP69
The Amberlite after " 3. process B " selection granularityTM IRP69
4. GRADISTAT is used, Blott, S.J.and Pye, K. (2001) GRADISTAT:For analyzing loose sink
The grain size distribution of starch and the software kit of statistics, to determine D10、D50And D90。Earth Surface Processes and
Landforms 26,1237-1248。
Table 7:Load the grain size analysis (wherein selecting process A and B) of resin
1. " the Amberlite after process A " selection granularitiesTM IRP69
The Amberlite after " 2. process B " selection granularityTM IRP69
3. GRADISTAT is used, Blott, S.J.and Pye, K. (2001) GRADISTAT:For analyzing loose sink
The grain size distribution of starch and the software kit of statistics, to determine D10、D50And D90。Earth Surface Processes and
Landforms 26,1237-1248。
Observe influence of the drug-resin ratio to the efficiency of loaded medicine.As a result it is shown in table 8 below and 9.
Table 8:Influence of the drug-resin ratio of batch to medicine loading procedure is loaded for representative drugs
Table 9:Drug-resin ratio loads the general introduction of process to medicine
1. based on the PHENYLEPHRINE HYDROCHLORIDE meter in slurries.
2. it is based on sequestered neo-synephrine meter.
Neo-synephrine analysis method-for the measurement of table 8 and 9
Sample preparation
1. accurate weigh the appropriate resin acid neo-synephrine sample with coating (comprising the hydrochloric acid deoxidation equivalent to 25mg
Adrenaline) and the sample weighed is transferred in 500mL volumetric flasks.
2. add 400mL diluents (1N HCl);Low-speed oscillation is not less than 2 hours on platform rocker.
3. in order to ensure particle is not gathered in above solvent levels, particle is flushed in solution using diluent.
4. it is diluted to scale using diluent and is sufficiently mixed..
5. use 0.45 μm of miillpore filter Kynoar syringe filter or equivalents filtering aliquot.To
Remainder is collected into before the HPLC bottles for analysis, about discharges 5mL filtrates first.
The analysis of neo-synephrine
Under the conditions of similar to those set forth below, by standard items, (the 0.05mg/mL hydrochloric acid in 1N HCl deoxygenates kidney
Upper parathyrine) and sample be injected on suitable HPLC system.Parameter can be changed to optimize chromatography.If meet system suitability
Specification, then analysis result is effective.
HPLC chromatogram separation condition
The analysis of dissolution of sample 4- pharmacokinetic materials
Using the method described in example 2, the first pharmacokinetics, the second pharmacokinetics and medicine for example 5 are analyzed
Imitate the dissolution rate of 0 to 8 hour of the resin acid neo-synephrine particle of dynamic (dynamical) band coating.As a result it is shown in table 10 below A.
Table 10A:Analysis of dissolution (50rpm)
Using methods described below, equally analyze the first pharmacokinetics for example 5, the second pharmacokinetics and
The dissolution rate of 0 to 8 hour of the resin acid neo-synephrine particle of the band coating of pharmacodynamics.As a result it is shown in table 10 below B
In.
Dissolution method, USP instruments 2 (blade), 75rpm
1. checking dissolution medium temperature has reached desired value.
Included 2. sample to be added to and (is directly appended to using suitable pipe in medium solution on the surface of medium solution)
The container of 750mL 0.1N hydrochloric acid and start dissolution rate test, wherein paddle speed is 75rpm.1 is operated in 0.1N hydrochloric acid
After hour, the sample of 1 hour is taken out, and buffer rank is entered by the tertiary sodium phosphate for the 0.20M for adding 250mL immediately
Section.The pH of medium should be 6.8 ± 0.05.
3. respectively 1 hour, 3 hours, 6 hours (optional) and after 8 hours, 10mL dissolution is taken out from each container
Spend sample solution.Filter (10 μm) filtered sample solution is flowed completely out by Varian.
4. compare the UV absorbances of the neo-synephrine of institute's dissolution and the UV extinctions of standard liquid under 274nm wavelength
Spend the amount of the neo-synephrine of dissolution to determine.
The amount of the neo-synephrine of institute's dissolution can also be used neo-synephrine analysis method to determine.
5. the amount in the dissolution of each time point institute is corrected by the amount of the addition taking-up at the point position of 3,6 and 8 hours.Pin
Centre is sampled, uses DISSL programs (or equivalents) or manual correction.
Table 10B:Analysis of dissolution (75rpm)
Stability analysis
For the resin acid of the band of the first pharmacokinetic for example 5 and the second pharmacokinetic coating
Neo-synephrine particle, analyze its placed 1 month under conditions of 25 DEG C and 60% relative humidity and at 40 DEG C and
Stability after being placed 1 month under conditions of 75% relative humidity.For whole samples, 3- hydroxy benzaldehydes contain
Amount is less than or equal to 0.5%;The isomers of neo-synephrine 4,6 (hydrochloric acid N- methyl -4,6- dihydroxy -1,2,3,4- tetrahydroxys
Isoquinolines) and the isomers of neo-synephrine 4,8 (N- methyl -4,8- dihydroxy -1,2,3,4- tetrahydroxys isoquinolines) it is small
In or equal to 2.0%.Place 1 month under circumstances, the amount for measuring the total degradation product related to neo-synephrine is small
In or equal to 2.0%.
Degradation products method
Sample preparation for degradation products method
1. accurate weigh the appropriate resin acid neo-synephrine sample with coating (comprising the hydrochloric acid deoxidation equivalent to 25mg
Adrenaline) and the sample weighed is transferred in 500mL volumetric flasks.
2. add 400mL diluents (1N HCl);Low-speed oscillation is not less than 2 hours on platform rocker.
3. in order to ensure particle is not gathered in above solvent levels, particle is flushed in solution using diluent.
4. it is diluted to scale with diluent and is sufficiently mixed.
5. use 0.45 μm of miillpore filter Kynoar syringe filter or equivalents filtering aliquot.To
Remainder is collected into before the HPLC bottles for analysis, 5mL filtrates before about discharging.
Analysis for the neo-synephrine of degradation products method
Under the conditions of similar to those set forth below, by standard items, (the 0.00025mg/mL hydrochloric acid in 1N HCl is gone
Oxygen adrenaline) and sample be injected on suitable HPLC system.Parameter can be changed to optimize chromatography.If meet that system is fitted
With property specification, then analysis result is effective.
HPLC chromatogram separation condition
Example 5:Clinical research
Carry out pharmacokinetics (PK) research twice and a pharmacodynamics (PD) is studied.
A.First pharmacokinetic
Experimental research is carried out to 16 persons under inspection, to determine the extended release neo-synephrine of the band coating derived from example 1
Particle and derived from example 2 band coating extended release resin acid neo-synephrine particle pharmacokinetic curve, biological utilisation
Degree and metabolism.Person under inspection is specified to receive four treatments after overnight fasted.Eliminated the need for seven days between 4 cycles.At two kinds
In the case of, the particle that will be equivalent to the band coating of the PHENYLEPHRINE HYDROCHLORIDE of 20mg dosage is placed in apple sauce and is administered to health
Person under inspection.In addition, extended release resin acid neo-synephrine particle and the commercially available combination of releasing liquid of the evaluation derived from example 2.
In combined therapy scheme, the resin acid neo-synephrine particle of the band coating of 15mg PHENYLEPHRINE HYDROCHLORIDEs will be equivalent to
It is placed in apple sauce and applies, and the 10mL liquid equivalent to 5mg PHENYLEPHRINE HYDROCHLORIDEs is applied by oral cavity syringe.
The extended release tree that the extended release neo-synephrine particle that band derived from example 1 is coated and the band derived from example 2 are coated
Resin acid neo-synephrine particle and McNeil-PPC, Inc. Non-Drowsy Children SudafedNasal cavity subtracts
Congested agent liquid (PHENYLEPHRINE HYDROCHLORIDE 2.5mg/5mL) is compared.Table 11 summarizes the first pharmacokinetic
In therapeutic scheme.
Table 11
[1]The unit dose of ER resin acid neo-synephrine particles of the about 84.2mg with coating is equivalent to 20mg hydrochloric acid
The dosage of neo-synephrine.About 63.2mg with coating ER resin acid neo-synephrine particles unit dose equivalent to
The dosage of 15mg PHENYLEPHRINE HYDROCHLORIDEs, and for the accumulated dose equivalent to 20mg PHENYLEPHRINE HYDROCHLORIDEs, Hou Zhedan
Position dosage is applied with the liquid 2.5mg/5mL of 10mL neo-synephrines.
Only before medication, ER resin acid neo-synephrine particles and ER hydrochloric acid that the band of the amount measured is coated deoxygenate
Adrenaline particle is folded to in the ounce cups of apple sauce 4, is then administered orally.These single doses are swallowed with 240mL water
Amount, rather than chew.PHENYLEPHRINE HYDROCHLORIDE liquid is administered orally using oral cavity syringe.For normative references therapeutic scheme
The condition of administration, first with 4 ounces of the cup with apple sauce and the liquid of 240mL water oral 10mg dosage twice.
After taking the medication at the particular point in time after 8 or 16 hours, a series of blood sample collections to K3-EDTA are managed
In.
B.Second pharmacokinetic
Carry out the second experimental research:(i) measure 30mg neo-synephrines whether can reach similar to interval 4 hours to
Give the maximum drug concentration for releasing neo-synephrine of 10mg dosage twice;(ii) evaluate 20mg neo-synephrines and
The ER PK distributions of 1300mg paracetamol and bioavilability.
The second experimental research is carried out for 20 persons under inspection, to determine the pharmacokinetic curve of following material, biology
Availability and metabolism:(1) the extended release resin acid of (a) equivalent to the coating of the band derived from example 2 of 15mg PHENYLEPHRINE HYDROCHLORIDEs
Neo-synephrine particle, (b) prolong equivalent to the 10mL neo-synephrines liquid and (c) 1300mg of 5mg neo-synephrines
Release the combination of paracetamol;(2) (a) is equivalent to the coating of the band derived from example 2 of 22.55mg PHENYLEPHRINE HYDROCHLORIDEs
The neo-synephrine liquid of extended release resin acid neo-synephrine particle and (b) equivalent to 7.5mg PHENYLEPHRINE HYDROCHLORIDEs
Combination;(3) (a) equivalent to 20mg PHENYLEPHRINE HYDROCHLORIDEs neo-synephrine liquid and (b) 1300mg extended releases to second
The combination of acylamino- phenol;And (4) equivalent to the neo-synephrine liquid of 20mg PHENYLEPHRINE HYDROCHLORIDEs.Table 12 summarizes
Therapeutic scheme in second pharmacokinetic.
Table 12
2Extended release Actamin Extra preparation is can beIdentical particle system commercially available Arthritis
Agent.
At the particular point in time after 12 or 20 hours, by a series of blood sample collections into K3-EDTA pipes.
As a result
The result of PK researchs is shown in Fig. 1-11 and table 13 below.
The comparison of the mean parameter of the pharmacokinetic of table 13-the first
Pay attention to:The AUC of therapeutic scheme A, B and C=more than 16 hours.AUCs of the therapeutic scheme D=more than 8 hours
Numeral is rounded
In a word, as a result show:
The Cmax of ER-IR blends comprising 20mg neo-synephrines is the 50% of 10mg dosage IR, and its
AUCinf is more than 15% (20mg) of 10mg dosage IR twice.
The Cmax of ER-IR blends comprising 30mg neo-synephrines is the 85% of 10mg dosage IR, and its
AUCinf is more than 61% (20mg) of 10mg dosage IR twice.
The Cmax of ER-IR blends comprising 20mg neo-synephrines and 1300mg paracetamol is 10mg dosage
The 80% of neo-synephrine IR, and its AUCinf is more than 22% (20mg) of 10mg dosage IR twice.
As a result show:The effect of preparation of the present invention, has exceeded the period extended.
These results also show:The preparation of the present invention can match the time of extended release paracetamol.
As a result also indicate:When neo-synephrine is combined with paracetamol, neo-synephrine exposure increase is simultaneously
And the PK curves of neo-synephrine are that the neo-synephrine for releasing dosage makes moderate progress relative to 10mg.This is probably because competing
Strive intestinal wall metabolism and cause the larger absorption of neo-synephrine and do not influence paracetamol;And delayed release dosage system provides
The larger absorption of neo-synephrine, because avoiding the intestinal wall metabolism in lower gastrointestinal tract.
C.Drug effect power Journal of Sex Research
Random, double blinding, placebo-controlled study are carried out, to determine neo-synephrine and neo-synephrine-to acetyl
Amino phenols delayed release dosage system is to because of the person under inspection of congested caused by the infection of the upper respiratory tract and pain symptom the effect of.Evaluation
The ER of ER, 45mg dosage of the 30mg dosage and ER with the 30mg dosage of 1300mg paracetamol co-administration, and
And compared with placebo.In each example, the ER resin acid neo-synephrine particles of the band coating of the present invention are used.Tight
Weight degree scoring ((1) airtight/congested nose;(2) sinus pressure/tenderness;The congested obstruction 0 to 12 in head is small in (3) 1 days
When) in performed respectively relative to placebo 30mg dosage ER, 45mg dosage ER and be total to 1300mg neo-synephrines
With the ER for the 30mg dosage applied.
Examples detailed above is not intended to limit the scope of the present invention, and the scope of the present invention can provide in detail in the claims.Tool
Say body, according to above disclosure it will be recognized by those skilled in the art a variety of equivalents and alternative form, and this
It is also within the scope of the present invention.
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Claims (1)
- A kind of 1. extended release particle, wherein the extended release particle includes starch, neo-synephrine and ethyl acrylate and methyl The copolymer of methyl acrylate, wherein the starch, neo-synephrine and ethyl acrylate and methyl methacrylate Copolymer is coated with least two coatings, wherein the first coatings include ethyl cellulose, tributyl 2-acetylcitrate and hard Fatty acid magnesium, and wherein the second coatings include the copolymer and ethyl cellulose of ethyl acrylate and methyl methacrylate Aqueous dispersion.
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PCT/US2014/019311 WO2014149529A1 (en) | 2013-03-15 | 2014-02-28 | Coated phenylephrine particles and use thereof in pharmaceutical formulations |
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HUP0302631A2 (en) * | 2000-03-30 | 2003-11-28 | Bristol-Myers Squibb Co. | Sustained release beadlets containing stavudine |
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BRPI0915411A2 (en) * | 2008-06-26 | 2015-11-03 | Mcneil Ppc Inc | coated particles containing pharmaceutically active agents |
WO2012020097A2 (en) * | 2010-08-13 | 2012-02-16 | Euro-Celtique S.A. | Use of binders for manufacturing storage stable formulations |
RU2477741C1 (en) * | 2012-04-27 | 2013-03-20 | Юрий Васильевич Захаров | Mulching composition (versions) |
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2013
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2014
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2016
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4917900A (en) * | 1987-03-27 | 1990-04-17 | Burroughs Wellcome Co. | Controlled release formulations containing zidovudine |
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RU2015144045A (en) | 2017-04-20 |
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AU2014238062B2 (en) | 2018-11-29 |
PH12015502015A1 (en) | 2016-01-11 |
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CN105246466A (en) | 2016-01-13 |
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WO2014149529A1 (en) | 2014-09-25 |
EP2968188A1 (en) | 2016-01-20 |
US20140271893A1 (en) | 2014-09-18 |
AU2014238062A1 (en) | 2015-09-17 |
BR112015022945B1 (en) | 2022-11-01 |
PH12015502015B1 (en) | 2016-01-11 |
JP2016516029A (en) | 2016-06-02 |
AR095526A1 (en) | 2015-10-21 |
HK1219886A1 (en) | 2017-04-21 |
BR112015022945A2 (en) | 2017-07-18 |
NZ712318A (en) | 2020-05-29 |
IL241051B (en) | 2018-06-28 |
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